title: CDKN2B expression in adipose tissue of familial combined hyperlipidemia patients.
abstract: The purpose of this study was to determine the core biological processes perturbed in the subcutaneous adipose tissue of familial combined hyperlipidemia (FCHL) patients. Annotation of FCHL and control microarray datasets revealed a distinctive FCHL transcriptome, characterized by gene expression changes regulating five overlapping systems: the cytoskeleton, cell adhesion and extracellular matrix; vesicular trafficking; lipid homeostasis; and cell cycle and apoptosis. Expression values for the cell-cycle inhibitor CDKN2B were increased, replicating data from an independent FCHL cohort. In 3T3-L1 cells, CDKN2B knockdown induced C/EBPα expression and lipid accumulation. The minor allele at SNP site rs1063192 (C) was predicted to create a perfect seed for the human miRNA-323b-5p. A miR-323b-5p mimic significantly reduced endogenous CDKN2B protein levels and the activity of a CDKN2B 3'UTR luciferase reporter carrying the rs1063192 C allele. Although the allele displayed suggestive evidence of association with reduced CDKN2B mRNA in the MuTHER adipose tissue dataset, family studies suggest the association between increased CDKN2B expression and FCHL-lipid abnormalities is driven by factors external to this gene locus. In conclusion, from a comparative annotation analysis of two separate FCHL adipose tissue transcriptomes and a subsequent focus on CDKN2B, we propose that dysfunctional adipogenesis forms an integral part of FCHL pathogenesis.
authors.affiliation: Medical Research Council, Clinical Sciences Centre, Hammersmith Hospital, London, United Kingdom.
authors.forename: Stuart D
authors.initials: SD
authors.lastname: Horswell
authors.forename: Lee G D
authors.initials: LG
authors.lastname: Fryer
authors.forename: Claire E
authors.initials: CE
authors.lastname: Hutchison
authors.forename: Dlear
authors.initials: D
authors.lastname: Zindrou
authors.forename: Helen E
authors.initials: HE
authors.lastname: Speedy
authors.forename: Margaret-M
authors.initials: MM
authors.lastname: Town
authors.forename: Emma J
authors.initials: EJ
authors.lastname: Duncan
authors.forename: Rasheeta
authors.initials: R
authors.lastname: Sivapackianathan
authors.forename: Hetal N
authors.initials: HN
authors.lastname: Patel
authors.forename: Emma L
authors.initials: EL
authors.lastname: Jones
authors.forename: Adam
authors.initials: A
authors.lastname: Braithwaite
authors.forename: Max P A
authors.initials: MP
authors.lastname: Salm
authors.forename: Claire K Y
authors.initials: CK
authors.lastname: Neuwirth
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Potter
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Anderson
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Taylor
authors.forename: Mary
authors.initials: M
authors.lastname: Seed
authors.forename: D John
authors.initials: DJ
authors.lastname: Betteridge
authors.forename: Martin A
authors.initials: MA
authors.lastname: Crook
authors.forename: Anthony S
authors.initials: AS
authors.lastname: Wierzbicki
authors.forename: James
authors.initials: J
authors.lastname: Scott
authors.forename: Rossi P
authors.initials: RP
authors.lastname: Naoumova
authors.forename: Carol C
authors.initials: CC
authors.lastname: Shoulders
mesh_terms: D041721:3T3-L1 Cells; D050156:Adipogenesis / Q000235:genetics; D000273:Adipose Tissue / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006239:Haplotypes; D006801:Humans; D006950:Hyperlipidemia, Familial Combined / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged
chemical_list: D050762:Cyclin-Dependent Kinase Inhibitor p15
keywords: adipogenesis; cell-cycle; microarray